4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid ester represented General Formula (11):
                wherein R1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group which may be substituted or an aralkyl group which may be substituted; R8 represents an amino-protecting group selected from among an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group which may be substituted, an aralkyl group which may be substituted, an acyl group or an alkoxycarbonyl group; and R9 represents an alkyl group which may be substituted, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group which may be substituted, an aralkyl group which may be substituted, an acyl group or a carbamoyl group,is useful as an intermediate in the synthesis of drugs such as anti-influenza drugs (see WO99/33781 Gazette).        
Conventional processes for producing 4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid esters include (i) a process in which cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester represented by Formula (9):
                wherein R1 and R8 are defined as above,is reacted with a nitro compound and phenyl isocyanate (see WO99/33781 Gazette), and (ii) a process in which a cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester of Formula (9) is reacted with an aldoxime, N-chlorosuccinimide and a base (see WO99/33781 Gazette).        
These processes both have drawbacks, however, in that they require a difficult after-treatment in order to isolate the target compound, and process (i) involves the use of phenyl isocyanate, which is unstable in water and difficult to handle, while process (ii) involves the use of relatively expensive N-chlorosuccinimide. These problems make these processes unsuited to industrial applications.
Also, a methyl ester encompassed by the raw material cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester represented by Formula (9) is produced by allowing a methanol solution of hydrogen chloride to react with the 2-azabicyclo[2.2.1]hept-5-en-3-one of Formula (1) (i.e., by conducting methanolysis of the 2-azabicyclo[2.2.1]hept-5-en-3-one of Formula (1)):
then removing the methanol, recrystallizing the residue with ether to form cis-4-amino-2-cyclopentene-1-carboxylic acid methyl ester hydrochloride, and then allowing this to react with a base and an amino-protecting group introducing compound (protectant) (see WO99/33781 Gazette).
In this process, however, a methanol solution of hydrogen chloride is prepared in advance, and the bicyclic compound of Formula (1) is added to and reacted with this solution, so there are various drawbacks, eg., (i) the solubility of hydrogen chloride in methanol is low, so a large quantity of methanol must be used, and the volumetric efficiency of the reactor is poor, and (ii) the hydrogen chloride, which theoretically only needs to be used in an amount of 1 equivalent, is used in an amount of 2 or more equivalents in order to make the reaction proceed more quickly. Consequently, this process is unsatisfactory for the purposes of industrial-scale production.
Also, the cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester of Formula (9) is such that the carbon atoms in the one and four positions of the cyclopentene ring are asymmetric carbons, and there are therefore compounds represented by Formula (9a) of (1S, 4R) absolute configuration, or by Formula (9b) of (1R, 4S) absolute configuration:
                wherein R1 and R8 are defined as above.        
These compounds are all useful as intermediate raw materials for pharmaceuticals and so forth, in particular, the carboxylic acid esters of Formula (9a) are known to be useful as a raw material in the synthesis of BCX-1812 (3-[1-(acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)-amino]-2-hydroxycyclopentanecarboxylic acid), which is promising as an anti-influenza drug.
The methyl esters encompassed by these optically active carboxylic acid esters of Formula (9a) or (9b) have been conventionally produced by using a microorganism or enzyme to resolve (±)-2-azabicyclo[2.2.1]hept-5-en-3-one to obtain the optically active 2-azabicyclo[2.2.1]hept-5-en-3-one of Formula (1), subjecting this compound to methanolysis to prepare an optically active cis-4-amino-2-cyclopentene-1-carboxylic acid methyl ester, and then reacting this with a base and an amino-protecting group introducing compound (protectant) (see WO99/33781 Gazette). However, special microorganisms or enzymes must be used in the optical resolution of the optically active 2-azabicyclo[2.2.1]hept-5-en-3-one of Formula (1), and because the reaction substrate concentration was low, the reactor efficiency was also low, and the reaction time was long, among other problems. Accordingly, an optically active 2-azabicyclo[2.2.1]hept-5-en-3-one cannot be easily obtained, and as a result, this conventional process cannot be considered industrially advantageous for the production of optically active cis-4-amino-2-cyclopentene-1-carboxylic acid esters.
It is an object of the present invention to provide a process that allows the industrially advantageous production of 4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid esters, and particularly optically active forms thereof, and to provide a process that allows the industrially advantageous production of salts of cis-4-amino-2-cyclopentene-1-carboxylic acid ester that is a raw material in the production of 4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid esters.